In this application we introduce a novel family of molecules, the PLUNC protein family. PLUNC stands for palate, lung and nasal epithelium clone, as first named in mice. Genomic surveys predict at least nine of these proteins in humans and multiple homologs have been identified in other mammals such as rats, mice and cows. All are small, secreted proteins. Several lines of evidence support the PLUNCs as a discrete mammalian gene family with a role in innate immunity. These include their conserved genomic locus, their similar intron-exon structure, their tissue-specific expression patterns and their predicted protein folds. Specifically, the three-dimensional structure of the PLUNCs is similar to that of an important immune defender, BPI (bactericidal/permeability-increasing protein). BPI dampens the body's response to infection by binding to lipopoylsaccharide (LPS), a component of the outer wall of Gram-negative bacteria. BPI neutralizes LPS and reduces the risk of catastrophic inflammatory responses, including septic shock and death. Given the similarity of PLUNCs to BPI, we propose three specific aims to understand more about this poorly known but diverse mammalian protein family: 1) locate the tissue-specific expression of PLUNC genes in mice, 2) construct mammalian cell lines that secrete multiple isoforms of PLUNC, and 3) test whether these secreted proteins can bind LPS, removing it from the inflammatory cascade. Taken together, the PLUNC proteins represent a novel family of therapeutic targets for the study of innate immunity and the treatment of infection.